Occlusion of a Vortex Vein After Treatment With Half-Fluence Photodynamic Therapy Combined With Intravitreal Aflibercept Injection for Pachychoroid Neovasculopathy

Photodynamic therapy (PDT) is a treatment option for pachychoroid diseases such as central serous chorioretinopathy (CSC), pachychoroid neovasculopathy (PNV), polypoidal choroidal vasculopathy (PCV), and peripapillary pachychoroid syndrome (PPS). On the other hand, morphological changes of choroidal vessels in the irradiated field after PDT have also been discussed, with occlusion of choriocapillaris and stenosis of choroidal middle and large vessels being reported. Here, we report a case of vortex vein occlusion after half-fluence PDT (HF-PDT) combined with an anti-vascular endothelial growth factor (VEGF) agent for PNV. In this case, HF-PDT achieved complete occlusion of PNV; in addition, a vortex vein that flowed in PNV but was located outside the PDT irradiation field was fully occluded three months post-treatment. At the occluded site of the vortex vein, indocyanine green video angiography revealed pulsation downstream of the vortex vein. Such occlusion of a large vessel by HF-PDT has not been reported previously. Occlusion could be induced by two factors: the potentiality of PDT and risk factors for thromboembolism, such as older age, smoking, and arrhythmia. Further studies are required to determine the mechanisms of these large vessel occlusions.

Currently, anti-vascular endothelial growth factor (VEGF) therapy is the gold standard for nAMD, and its efficacy for PNV has been reported [3][4][5]. However, more extensive injections of anti-VEGF compared to PCV may be required to treat PNV. Photodynamic therapy (PDT) is one of the treatment options for not only CSC but also nAMD; PDT therapy can regress MNV and reduce vascular permeability of the choriocapillaris and choroidal thickness, which can contribute to the absorption of retinal fluid [6]. PDT combined with anti-VEGF agents appears to be a more potent tool for PCV treatment. The endovascular valve edge-to-edge repair study (EVEREST) II trial [7] revealed that the combination therapy of PDT and ranibizumab for PCV was superior to ranibizumab alone with respect to improvement of visual acuity and frequencies of polypregression. Recently, half-fluence PDT (HF-PDT) combined with anti-VEGF agents was also applied to patients with PNV to stabilize MNV and the choroid [8].
After PDT treatment, a circumscribed occlusion of the choriocapillaris was identified in the area where PDT was exposed using indocyanine green angiography (IA) [9]. In this study, eyes were surgically removed seven days after PDT, and a histological study of the PDT exposed area also revealed an occluded choriocapillaris filled with emboli, which was accompanied by deformed erythrocytes, degranulated platelets, and fibrin. These results suggest that the essential effect of PDT is the clogging of capillary vessels in the choroid.
In this case presentation, we present an unusual case in which a large vortex vein was occluded after HF-PDT with aflibercept intravitreal injection in a patient with PNV.

Case Presentation
An 89-year-old man was referred to our hospital because of impaired vision in the right eye. He had a medical history of arrhythmia (not medicated) and benign prostatic hyperplasia. His smoking history was 12 cigarettes per day for 30 years (from the age of 20 to 50 years). Best-corrected visual acuity was 20/32 in the right eye and 20/20 in the left eye. Optical coherence tomography (OCT) revealed serous retinal detachment accompanied by flat retinal pigment epithelial detachment in the right macula, in addition to a thickened choroid-associated dilatation of outer choroidal vessels in the same eye ( Figure 1B). OCT angiography (OCTA) revealed choroidal neovascularization beneath the pigment epithelial detachment ( Figure 1C). IA also identified choroidal neovascularization in the same area as OCTA, and dilated vortex veins adjacent to the CNV were detected ( Figure 1D). Choroidal vascular hyperpermeability was observed in the late stage of IA. We diagnosed PNV and performed reduced fluence PDT (RF-PDT) with intravitreal aflibercept injection. Three months after treatment, the serous retinal detachment disappeared, and choroidal thickening decreased (Figure 2A). The CNV was successfully regressed and reduced in both IA and OCTA. IA was used to detect a circumscribed hypofluorescent area where HF-PDT was applied ( Figure 2B, 2C).  Three months post-treatment, IA also revealed occlusion of a vortex vein that branched in the inferior posterior region, outside the irradiated area ( Figure 3A, 3B). A complete interruption in the vortex vein was observed without a downstream flow of the vessel in a movie of the IA (Heidelberg Engineering, Heidelberg, Germany) (Video 1). Interestingly, pulsation of the vortex vein at this portion was also detected, and the blood seemed to stream inversely when compared to the bloodstream at the initial visit. Fourteen months post-treatment, the IA movie revealed complete occlusion of the vortex vein, with no recanalization and no pulsation ( Figure 3C). Fortunately, no recurrence of MNV developed, the patient did not complain of any changes in vision during the follow-up period, and his final visual acuity remained unchanged at 20/32.

Discussion
This case suggests that PDT can cause not only clotting of capillary vessels but also occlusion of large choroidal vessels.
Vascular occlusion at the level of the choroidal capillary plate after PDT has been reported previously [9,10]; however, occlusion of large vessels, as observed in this study, has not been reported before.
Previous studies have identified that verteporfin is essentially taken up by abnormal neovascularization, leading to selective cytotoxicity of vascular endothelial cells through the production of oxidative radicals. This reactivity can cause regression of neovascularization and resolution of the leakage from the neovascular membrane [11][12][13].
On the other hand, PDT also affected normal choroidal vessels, specifically both normal choriocapillaris and middle and large choroidal vessels [10,14,15]. As mentioned in the introduction, the circumscribed hypofluorescent area where the PDT had been exposed was detected in IA after PDT treatment, and the area contained both normal and abnormal choroidal vessels [9]. OCT image analysis revealed thinning of the choroid after PDT treatment [16], and the vascular density in both the choriocapillaris and the middle layer of the choroid significantly decreased after the treatment. Moreover, the maximum vessel diameter in the outer choroidal layer in the area exposed to PDT was significantly reduced but not occluded [9]. In this case, occlusion of the large vortex vein outside the irradiated area could have been induced by three factors: the potentiality of PDT, the existence of a vessel branch traversing the irradiated area, which could have caused thromboembolism to the distal part, and risk factors for thromboembolism, such as older age, smoking, and arrhythmia [17].
On the other hand, indocyanine green angiography in the early phase showed hyperfluorescent plaque overlying a large caliber choroidal vessel in Figure 1D, which possibly corresponded to an anastomotic vessel connecting the upper and lower vortex veins [18]. In this case, the superior and inferior vortex veins were asymmetric. They seemed to be connected by anastomosis at the horizontal watershed zone. The superior vortex vein had a larger diameter, and the inferior vortex vein had a thinner diameter. Thus, the superior vortex vein should be responsible for compensatory venous flow before treatment. After treatment, blood flow seemed to return upward in a V-shape due to the trunk occlusion. The trunk of the inferior vortex vein could be no longer needed and considered to have been occluded by disuse.
With the detection of the occlusive vortex vein, a pulsation was detected downstream of the occlusive portion in the IA. Pulsation of the retinal artery was previously reported in cases with central retinal vein occlusion, and the authors concluded that pulsation meant a delay in the retinal bloodstream. In pachychoroid spectrum diseases, pulsation in the choroidal large vasculature has also been detected in treatment-naïve cases [19]. These results suggest that choroidal overload might be associated with the disturbance of choroidal circulation. In this case, the backflow of the vortex vein downstream of the occlusive portion may have led to turbulent flow in this area.

Conclusions
To the best of our knowledge, we report a first case in which a vortex vein located outside the irradiated area was occluded after HF-PDT combined with intravitreal aflibercept. At the occluded site of the vortex vein, indocyanine green video angiography revealed pulsation downstream of the vortex vein. Pulsation on IA can be used as a biomarker to suggest an overload of choroidal circulation.